Cannabis is the most commonly used illicit drug worldwide. There is increasing recognition of a cannabis dependence syndrome that includes both tolerance and withdrawal. Furthermore, the rates of cannabis use have increased during early adolescence, when the developing brain might be especially susceptible to environmental exposures. This public health concern is further fueled by the fact that the potency of cannabis seems to have increased over the past decades. There is also increasing demand for treatments for cannabis use disorders. Therefore, it is important to fully understand the consequences of cannabis dependence in humans on the brain cannabinoid system. Exogenous cannabinoids produce their psychoactive effects via the activation of brain CB1 receptors (CB1R). Repeated exposure to cannabis and CB1R agonists is associated with the development of tolerance and dependence. While this has been shown to be accompanied by CB1R downregulation in animals, it has yet to be demonstrated in humans, in vivo. The discontinuation of chronic, heavy exposure to cannabinoids in both humans and animals, and the administration of CB1R antagonists to cannabinoid dependent animals, is associated with a clear withdrawal syndrome. Finally, with prolonged abstinence there seems to be a reversal of tolerance, which in animals has been shown to be accompanied by normalization of CB1Rs. However, this has yet to be demonstrated in humans, either post mortem or in vivo. The aim of the current proposal is to use the validated CB1R PET ligand [11C]OMAR and High Resolution Research Tomography (HRRT) to measure CB1R availability in vivo in cannabis-dependent individuals at 1) baseline, 2) following brief (48 hours) confirmed inpatient abstinence (at the peak of cannabis withdrawal and CB1R downregulation), and 3) after prolonged (4 weeks) confirmed outpatient abstinence. It is expected that at baseline, cannabis-dependent subjects (n=8) will have lower CB1R availability than matched controls (n=8), but this difference will no longer be present after 4 weeks of abstinence. Furthermore, cannabis-dependent subjects will have lower CB1R availability during acute cannabis withdrawal relative to their baseline state. Taken together, it is hoped that data from this study will elucidate the neurobiological consequences of chronic cannabis consumption and its effect on CB1 receptors, and will shed new light on the status and function of CB1 receptors during active cannabis use, and withdrawal. PUBLIC HEALTH RELEVANCE: Little is known about the consequences of heavy cannabis use on the brain cannabinoid system. This grant application proposes to use brain imaging to study the changes in the brain cannabinoid receptor system as a result of heavy cannabis use, 2 days after stopping cannabis use and again after 4 weeks of abstinence from cannabis.